Øgaard Nadia, Reinert Thomas, Henriksen Tenna V, Frydendahl Amanda, Aagaard Emilie, Ørntoft Mai-Britt W, Larsen Marie Ø, Knudsen Anders R, Mortensen Frank V, Andersen Claus L
Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark.
Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Institute of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark.
Eur J Cancer. 2022 Mar;163:163-176. doi: 10.1016/j.ejca.2021.12.026. Epub 2022 Jan 22.
Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance.
499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test 'TriMeth'.
Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052).
Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.
在接受结直肠癌肝转移（CRLM）根治性切除术后两年内，近50%的患者会复发。由于缺乏证据，最佳监测策略尚不清楚。在此，我们通过与标准治疗监测并行进行系列循环肿瘤DNA（ctDNA）评估，探索改善术后CRLM监测的可能性。
使用肿瘤非特异性甲基化多重液滴数字PCR检测“TriMeth”对96例接受CRLM切除患者前瞻性收集的499份系列血浆样本进行分析。
术后或辅助化疗后有ctDNA的患者无复发生存期显著低于无ctDNA的患者（风险比[HR]4.5；P<0.0001和HR 8.4，P<0.0001）。ctDNA状态比标准临床风险因素和癌胚抗原更能预测复发。系列TriMeth分析在55.6%的ctDNA阳性患者中，在影像学复发前检测到ctDNA，提前时间长达10.6个月（中位3.1个月）。在监测期间，24%的患者CT扫描结果不明确，这与复发诊断的显著延迟相关（中位3.5个月对1.0个月，P<0.0001）。独特的是，CT扫描结果不明确时的ctDNA状态预测复发的阳性和阴性预测值分别为100%和75%（P=0.0003）。系列TriMeth分析允许评估ctDNA生长速率，并显示ctDNA快速生长与总生存期差相关（HR：1.6，P=0.0052）。
术后系列ctDNA分析具有很强的预后价值，并且比CRLM标准治疗监测工具对复发检测更敏感。总之，TriMeth为改善CRLM患者的术后监测提供了多个机会。
